Piperazinyl pyrimidine dione compounds selective for adrenoceptors

ABSTRACT

Compounds of Formula I and II and their pharmaceutically acceptable, salts, esters and prodrugs thereof are selective alpha-1D adrenoceptor anatagonists and may be useful for treating disease states.

This application claims the benefit of U.S. Provisional Application No.60/092,988, filed Jul. 16, 1998.

TECHNICAL FIELD

The present invention relates to compounds that are α_(1D) -adrenoceptorantagonists, pharmaceutical compositions containing these compounds, andmethods of treatment using these compounds.

BACKGROUND OF THE INVENTION

α₁ -Adrenergic receptors are widely distributed throughout both thecentral nervous system and the periphery where they mediate the effectsof epinephrine and norepinephrine on the sympathetic nervous system. α₁-Adrenoceptors play a central role in the maintenance of smooth muscletone in both the prostate and the cardiovascular system (Ruffolo, R. R.,Hieble, J. P. Pharmac. Ther. 1994, 61, 1-64). Antagonists of α₁-adrenoceptors have shown beneficial effects both on amelioratinghypertension and alleviating the symptoms of benign prostatichyperplasia (BPH) (Ruffolo, R. R., Bondinell, W., Hieble, J. P. J. Med.Chem. 1995, 38, 3681-3716) by producing a smooth muscle relaxant effectin the target organs resulting from blockade of vascular or prostatic α₁-receptors.

Recently, three distinct subtypes of the α₁ -adrenoceptor have beenidentified by both molecular biological (α_(1a), α_(1b), α_(1d)) andclassical pharmacological (α_(1A), α_(1B), α_(1D)) means. The functionalexpression of the α_(1D) -adrenoceptor subtype in various vascular bedshas been demonstrated (Villalobos-Molina, R., Ibarra, M. Eur. J.Pharmacol. 1996, 298, 257-263; Piascik, M. T. et al. J. Pharmacol. Exp.Ther. 1995, 275, 1583-1589; Kenny, B. A. et al. Br. J. Pharmacol. 1995,115, 981-986). Additionally, it has been shown that the α_(1D)-adrenoceptor plays a significant role in maintaining blood pressure(Zhou, L., Vargas, H. M. Eur. J. Pharmacol. 1996, 305, 173-176; Deng, X.F., Chemtob, S., Varma, D. R. Br. J. Pharmacol. 1996, 119, 269-276) andthat its role in maintaining blood pressure increases with the age ofthe mammal (Ibarra, M. et al. Eur. J. Pharmacol. 1997, 322, 221-224).Therefore, the utility of a selective α_(1D) -antagonist in thetreatment of hypertension is indicated (Deng et al.). Also,approximately 30% of the mRNA in the prostate encodes for the α_(1D)-adrenoceptor (Price, D. T. et al. J. Urol. 1993, 150, 546-541 whichsuggests a possible role in ameliorating the symptoms often associatedwith BPH. Additionally, it has been shown recently (Broten et al. TheFASEB Journal Abstracts Part 1, (1998), 12 (4) A445) that the α_(1D)-receptor is involved in mediating contractions associated with detrusorinstability secondary to bladder outlet obstruction. It has also beenshown recently that the α_(1D) -receptor is the predominant α₁ subtypepresent in the human bladder detrusor (Malloy, et al. in J. of Urology,(1998) 159, (5, Suppl.) 1263). The association of incontinence and theirritative symptoms of BPH with detrusor instability suggests that anα_(1D) -antagonist capable of inhibiting detrusor contractions would beuseful in the treatment of incontinence and BPH.

Russell and Press (U.S. Pat. No. 4,670,560 and J. Med. Chem. 1988, 31,1786) describe thienopyrimidine-2,4-dione derivatives which are α₁-antagonists and antihypertensive agents, and Meyer et al. (U.S. Pat.No. 5,521,181) describe phenyl substitutedhexahydrobenz[e]isoindolylthienopyrimidine-2,4-diones which are α₁-antagonists. However, these compounds are not selective for the aα_(1D) subtype.

The present invention relates to novel α_(1D) adrenoceptor antagonistcompounds, pharmaceutical compositions containing the compounds, andmethods of treatment using these compounds.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are α_(1D) -adrenoceptoranatagonists, pharmaceutical compositions contianing these compounds,and methods of treatment using these compounds.

The compounds of the present invention have the structure of Formula I##STR1## wherein R₁, R_(1'), and R_(1") are independently selected fromthe group consisting of (a) halo, (b) hydroxy, (c) nitro, (d) amino, (e)N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy, (h) carboxy, (i)O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl, (l)cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy, (q)alkynyloxy, (r) alkynyl, (s) alkoxycarbonyl, and (t) hydrogen wherein(j)-(s) can be optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of alkoxy, hydroxy,carboxy, O-protected carboxy, amino, N-protected amino, halo, hydroxy,and nitro;

n is 2-10; and

R₂ is ##STR2## wherein U, taken together with the carbon atoms to whichit is attached, forms a ring selected from the group consisting of

(a) a mono- or disubstituted five-membered heterocycle having fourcarbon atoms, two double bonds, and one heteroatom selected from thegroup consisting of --N(R₅)--, --O--, and --S-- wherein R₅ is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycle, and (heterocyclic)alkyl, and the mono- or di-substituentsare independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycle, and (heterocyclic)alkyl, with the proviso that at least oneof R₅, mono-, or disubstituents is cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocyclic, or (heterocyclic)alkyl;

(b) a mono- or disubstituted five-membered heterocycle having threecarbon atoms, two double bonds, and two heteroatoms selected from thegroup consisting of two nitrogen atoms, one oxygen atom and one nitrogenatom, and one sulphur atom and one nitrogen atom, and the mono- ordi-substituents are independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, and (heterocyclic)alkyl, with the proviso thatat least one of the mono- or di-substituents is cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl;and

(c) a mono- or disubstituted six-membered heterocycle containing threedouble bonds and either one, two, or three nitogen atoms, and the mono-or disubstituents are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, and (heterocyclic)alkyl, with the proviso thatat least one of the mono- or di-sustituents is cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl;and

wherein R₃ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, and cycloalkylalkyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention have the structure of Formula I##STR3## wherein R₁, R_(1'), and R_(1") are independently selected fromthe group consisting of (a) halo, (b) hydroxy, (c) nitro, (d) amino, (e)N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy, (h) carboxy, (i)O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl, (l)cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy, (q)alkynyloxy, (r) alkynyl, (s) alkoxycarbonyl, and (t) hydrogen wherein(j)-(s) can be optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of alkoxy, hydroxy,carboxy, O-protected carboxy, amino, N-protected amino, halo, hydroxy,and nitro;

n is 2-10; and

R₂ is ##STR4## wherein U, taken together with the carbon atoms to whichit is attached, forms a ring selected from the group consisting of

(a) a mono- or disubstituted five-membered heterocycle having fourcarbon atoms, two double bonds, and one heteroatom selected from thegroup consisting of --N(R₅)--, --O--, and --S-- wherein R₅ is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycle, and (heterocyclic)alkyl, and the mono- or di-sustituentsare independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycle, and (heterocyclic)alkyl, with the proviso that at least oneof R₅, mono-, or disubstituents is cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocyclic, or (heterocyclic)alkyl;

(b) a mono- or disubstituted five-membered heterocycle having threecarbon atoms, two double bonds, and two heteroatoms selected from thegroup consisting of two nitrogen atoms, one oxygen atom and one nitrogenatom, and one sulphur atom and one nitrogen atom, and the mono- ordi-substituents are independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, and (heterocyclic)alkyl, with the proviso thatat least one of the mono- or di-sustituents is cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl;and

(c) a mono- or disubstituted six-membered heterocycle containing threedouble bonds and either one, two, or three nitogen atoms, and the mono-or di-sustituents are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, and (heterocyclic)alkyl, with the proviso thatat least one of the mono- or di-sustituents is cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl;and

wherein R₃ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, and cycloalkylalkyl.

Another embodiment of the the present invention includes a compound ofFormula I wherein

U is ##STR5## wherein X is selected from the group consisting of--N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, and(heterocyclic)alkyl, with the proviso that at least one of R₅, R₆ and R₇cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl; or a pharmaceutically accceptable salt, ester, orprodrug thereof

Another embodiment of the present invention includes a compound ofFormula I wherein

U is ##STR6## wherein X is selected from the group consisting of--N(R₅)--, --O--, and --S--, n is 2-5, R₃ is hydrogen or alkyl, R₁,R_(1'), and R_(1") are independently selected from hydrogen and alkoxy,and R₅, R₆ and R₇ are independently hydrogen or aryl with the provisothat at least one of R₅, R₆ and R₇ is aryl; or a pharmaceuticallyacceptable salt, ester or prodrug thereof.

Another embodiment of the present invention includes a compound or apharmaceutically acceptable salt, ester or prodrug of Formula I, wherein

U is ##STR7## wherein X is selected from the group consisting of--N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, and(heterocyclic)alkyl, with the proviso that at least one of R₅, R₆ and R₇is cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl.

Another embodiment of the present invention includes a compound ofFormula I wherein

U is ##STR8## X is selected from the group consisting of --N(R₅)--,--O--, and --S--, n is 2-5, R₃ is hydrogen or alkyl, R₁, R_(1'), andR_(1") are independently selected from hydrogen and alkoxy, and R₅, R₆and R₇ are independently hydrogen or aryl with the proviso that at leastone of R₅, R₆ and R₇ is aryl; or a pharmaceutically acceptable salt,ester or prodrug thereof.

Another embodiment of the present invention includes a compound or apharmaceutically acceptable salt, ester or prodrug of Formula I wherein

U is ##STR9## wherein X is selected from the group consisting of--N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, and(heterocyclic)alkyl, with the proviso that at least one of R₅, R₆ and R₇cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl.

Another embodiment of the present invention includes a compound or apharmaceutically acceptable salt, ester or prodrug of Formula I wherein

U is ##STR10## wherein X is selected from the group consisting of--N(R₅)--, --O--, and --S--, n is 2-5, R₃ is hydrogen or alkyl, R₁,R_(1'), and R_(1") are independently selected from hydrogen and alkoxy,and R₅, R₆ and R₇ are independently hydrogen or aryl, with the provisothat at least one of R₅, R₆ and R₇ is aryl.

Another embodiment of the present invention includes a compound ofFormula I or a pharmaceutically acceptable salt, ester or prodrugthereof wherein n is 2-5, U is a mono- or disubstituted five-memberedheterocycle having three carbon atoms, two double bonds, and twoheteroatoms selected from the group consisting of two nitrogen atoms,one oxygen atom and one nitrogen atom, and one sulphur atom and onenitrogen atom, and the mono- or di-sustituents are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, and(heterocyclic)alkyl, with the proviso that at least one of the mono- ordi-sustituents is cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclic, or (heterocyclic)alkyl; and R₁, R_(1'), and R_(1") areindependently selected from (a) halo, (b) hydroxy, (c) nitro, (d) amino,(e) N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy, (h) carboxy,(i) O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl, (l)cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy, (q)alkynyloxy, (r) alkynyl, and (s) alkoxycarbonyl wherein (j)-(s) can beoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkoxy, hydroxy, carboxy,O-protected carboxy, amino, N-protected amino, halo, hydroxy, and nitro.

Another embodiment of the present invention includes a compound ofFormula I or a pharmaceutically acceptable salt, ester or prodrugwherein n is 2-5, U is a mono- or disubstituted six-membered heterocyclecontaining three double bonds and either one, two, or three nitogenatoms, and the mono- or di-sustituents are independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, and (heterocyclic)alkyl,with the proviso that at least one of the mono- or di-sustituents iscycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl; and and R₁, R_(1'), and R_(1") are independentlyselected from the group consisting of (a) halo, (b) hydroxy, (c) nitro,(d) amino, (e) N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy,(h) carboxy, (i) O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl,(l) cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy,(q) alkynyloxy, (r) alkynyl, and (s) alkoxycarbonyl wherein (j)-(s) canbe optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkoxy, hydroxy, carboxy,O-protected carboxy, amino, N-protected amino, halo, hydroxy, and nitro.

Yet another embodiment of the present invention includes a compound ofFormula II ##STR11## or a pharmaceutically acceptable salt, ester orprodrug thereof, wherein R₁, R_(1'), and R_(1") are independentlyselected from the group consisting of (a) halo, (b) hydroxy, (c) nitro,(d) amino, (e) N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy,(h) carboxy, (i) O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl,(l) cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy,(q) alkynyloxy, (r) alkynyl, (s) alkoxycarbonyl, and (t) hydrogenwherein (j)-(s) can be optionally substituted with 1, 2, or 3substituents independently selected from the group consisting of alkoxy,hydroxy, carboxy, O-protected carboxy, amino, N-protected amino, halo,hydroxy, and nitro;

n is 2-5; and

R₂ is selected from the group consisting of ##STR12## wherein at eachoccurence X is selected from the group consisting of --N(R₅)--, --O--,and --S-- wherein R₅, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, and (heterocyclic)alkyl,with the proviso that at least one of R₅, R₆ and

R₇ is cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl, and R₃ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkylalkyl.

Yet another embodiment of the present invention includes a compound or apharmaceutically acceptable salt, ester or prodrug thereof of Formula IIwherein R₂ is ##STR13## wherein X is selected from the group consistingof --N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen and aryl with the provisothat at least one of R₅, R₆ and R₇ is aryl, and R₃ is selected from thegroup consisting of hydrogen and alkyl.

Yet another embodiment of the present invention includes a compound ofFormula II or a pharmaceutically acceptable salt, ester or prodrugwherein R₂ is ##STR14## wherein X is selected from the group consistingof --N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen and aryl with the provisothat at least one of R₅, R₆ and R₇ is aryl, and R₃ is selected from thegroup consisting of hydrogen and alkyl.

Yet another embodiment of the present invention includes a compound ofFormula II or a pharmaceutically acceptable salt, ester or prodrugwherein R₂ is ##STR15## wherein X is selected from the group consistingof --N(R₅)--, --O--, and --S-- wherein R₅, R₆ and R₇ are independentlyselected from the group consisting of hydrogen and aryl with the provisothat at least one of R₅, R₆ and R₇ is aryl, and R₃ is selected from thegroup consisting of hydrogen and alkyl.

Yet another embodiment of the present invention includes a compound ofFormula II or a pharmaceutically acceptable salt, ester or prodrugthereof wherein R₂ is ##STR16## wherein R₁, R_(1'), and R_(1") areindependently selected from the group consisting of hydrogen and alkoxy,n is 2, X is selected from the group consisting of --N(R₅)-- and --S--wherein R₅ , R₆ and R₇ are independently selected from the groupconsisting of hydrogen and aryl with the proviso that at least one ofR₅, R₆ and R₇ is aryl, and R₃ is hydrogen or alkyl.

Yet another embodiment of the present invention includes a compound or apharmaceutically acceptable salt, ester or prodrug wherein R₂ is##STR17## wherein R₁, R,_(1'), and R_(1") are independently selectedfrom the group consisting of hydrogen and alkoxy, n is 2, X is selectedfrom the group consisting of --N(R₅)-- and --S-- wherein R₅ , R₆ and R₇are independently selected from the group consisting of hydrogen andaryl with the proviso that at least one of R₅, R₆ and R₇ is aryl, and R₃is hydrogen or alkyl.

Yet another embodiment of the present invention includes a compound ofFormula II or a pharmaceutically acceptable salt, ester or prodrugthereof wherein R₂ is ##STR18## wherein R₁, R_(1'), and R_(1") areindependently selected from the group consisting of hydrogen and alkoxy,n is 2, X is selected from the group consisting of --N(R₅)-- and --S--wherein R₅ , R₆ and R₇ are independently selected from the groupconsisting of hydrogen and aryl with the proviso that at least one ofR₅, R₆ and R₇ is aryl and R₃ is hydrogen or alkyl.

In another embodiment of the invention is disclosed a method ofantagonizing α_(1D) -adrenoceptors in a host mammal, particularlyhumans, in need of such treatment by administering a therapeuticallyeffective amount of a compound of Formula I or II.

In yet another embodiment of the invention is disclosed a method oftreating benign prostatic hyperplasia, hypertension, detrusorinstability, and incontinence in a mammal, particularly humans, in needof such treatment by administering an effective amount of a compound ofFormula I or II.

In still yet another embodiment of the invention is disclosedpharmaceutical compositions which comprise a therapeutically effectiveamount of a compound of Formula I or II in combination with apharmaceutically effective carrier.

Definition of Terms

The term "alkenyl" refers to a monovalent straight or branched chaingroup of 2-10 carbons derived from a hydrocarbon having at least onecarbon--carbon double bond.

The term "alkenyloxy" as used herein refers to an alkenyl group of 3-10carbons attached to the parent molecular group through an oxygen atom.

The term "alkoxy" as used herein refers to an alkyl group as definedherein attacthed to the parent molecular group through an oxygen atom.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,t-butoxy, and the like.

The term "alkoxycarbonyl" refers to an ester group, i.e. an alkoxy groupattached to the parent molecular group through a carbonyl group.

The term "alkyl" or "loweralkyl" as used herein refers to a straight orbranched chain alkyl radical containing from 1 to 10 carbon atomsincluding, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl,2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl, and the like.

The term "alkylamino" as used herein refers to an amino group whereinone of the hydrogens has been replaced with an alkyl group.

The term "alkynyl" as used herein refers to a monovalent straight orbranched chain hydrocarbon of 2-10 carbons with at least onecarbon--carbon triple bond.

The term "alkynyloxy" as used herein refers to an alkynyl group of 3-10carbons attached to the parent molecular group through an oxygen atom.

The term "amino" as used herein refers to --NH₂.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclicring system having one or more aromatic rings including, but not limitedto, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl,indenyl and the like. Aryl groups can be unsubstituted or substitutedwith one, two or three substituents independently selected from thegroup consisting of loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro,carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition,substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" as used herein refers to an aryl group aspreviously defined, appended to a loweralkyl radical. Examples ofarylalkyl are benzyl, phenethyl, and the like.

The term "carboxy" as used herein refers to --CO₂ H.

The term "carboxaldehyde" as used herein refers to --CHO.

The term "carboxanide" as used herein refers to an amino, alkylamino, ordialkylamino group attached to the parent molecular group through acarbonyl group.

The term "cycloalkoxy" as used herein refers to an cycloalkyl group asdefined herein attached to the parent molecular group through an oxygenatom. Cycloalkoxy groups can be unsubstituted or substituted with one,two or three substituents independently selected from loweralkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl andcarboxamide.

The term "cycloalkyl" as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 to 3 rings including, but not limitedto, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and thelike. Cycloalkyl groups can be unsubstituted or substituted with one,two or three substituents independently selected from loweralkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl andcarboxamide.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl groupas defined herein appended to a loweralkyl radical. Cycloalkylalkylgroups include but are not limited to cyclopropylmethyl,cyclohexylethyl, and the like. Cycloalkylalkyl groups can beunsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy,amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro,carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

The term "dialkylamino" as used herein refers to an amino group whereineach of the hydrogens has been replaced with an alkyl group.

The term "halo" as used herein refers to F, Cl, Br and I.

The term "haloalkoxy" as used herein refers to a haloalkyl group asdefined herein attached to the parent molecular group through an oxygenatom.

The term "haloalkyl" as used herein refers to an alkyl group as definedherein to which is attached one or more halo substituents.

The terms "heterocyclic ring" or "heterocyclic" or "heterocycle" as usedherein refers to any 3- or 4-membered ring containing a heteroatomselected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-memberedring containing one, two or three nitrogen atoms; one nitrogen and onesulfur atom; or one nitrogen and one oxygen atom, or one sulphur atom,or one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-and 7-membered ring have 0-3 double bonds. The nitrogen heteroatoms canbe optionally quaternized. The term "heterocyclic" also includesbicyclic groups in which any of the above heterocyclic rings is fused toa benzene ring or a cyclohexane ring or another heterocyclic ring (forexample, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofurylor benzothienyl and the like). Heterocyclics include: azetidinyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, furyl, thienyl and benzothienyl.

Heterocyclics can be unsubstituted or monosubstituted or disubstitutedwith substituents independently selected from hydroxy, halo, oxo (═O),alkylimino (R*N═ wherein R* is a loweralkyl group), amino, alkylamino,dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl,arylalkyl, --COOH, --SO₃ H, nitro, and loweralkyl. In addition, nitrogencontaining heterocycles can be N-protected.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclicgroup as defined above appended to a loweralkyl radical as definedabove.

The term "hydroxy" as used herein refers to --OH.

The term "mercapto as used herein, refers to --SH.

The term "N-protected amino" or "N-protected nitrogen" as used hereinrefers to an amino group to which is attached an N-protecting ornitrogen-protecting group. The term "nitrogen protecting group" as usedherein, refers to those groups intended to protect an amino groupagainst undersirable reactions during synthetic procedures. N-protectinggroups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl,t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiralauxiliaries such as protected or unprotected D, L or D, L-amino acidssuch as alanine, leucine, phenylalanine, and the like; sulfonyl groupssuch as benzenesulfonyl, p-toluenesulfonyl and the like; carbamateforming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

The term "nitro" as used herein refers to --NO₂.

The term "O-protected carboxy" as used herein refers to an ester oramide group intended to protect a carboxy group against undersirablereactions during synthetic procedures. Additionally, a carboxyprotecting group can be used as a prodrug whereby the carboxy protectinggroup can be readily cleaved in vivo, for example, by enzymatichydrolysis, to release the biologically-active parent compound. Suchcarboxy protecting groups are well-known to those skilled in the art,having been extensively used in the protection of carboxyl groups in thepenicillin and cephalosporin fields as described in U.S. Pat. Nos.3,840,556 and 3,719,667, the disclosures of which are incorporatedherein by reference. Representative carboxy protecting groups are C₁ -C₈loweralkyl (e.g., methyl, ethyl or t-butyl and the like); arylalkyl suchas phenethyl or benzyl and substituted derivatives thereof such asalkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl such asphenylethenyl and the like; aryl and substituted derivatives thereofsuchas 5-indanyl and the like; dialkylaminoalkyl such as dimethylaminoethyland the like); alkanoyloxyalkyl groups such as acetoxymethyl,butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl,isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl,1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyland the like; cycloalkanoyloxyalkyl groups such ascyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like;aroyloxyalkyl such as benzoyloxymethyl, benzoyloxyethyl and the like;arylalkylcarbonyloxyalkyl such as benzylcarbonyloxymethyl,2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl orcycloalkyloxycarbonylalkyl such as methoxycarbonylmethyl,cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl and the like;alkoxycarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl such asmethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl,1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and thelike; aryloxycarbonyloxyalkyl such as 2-(phenoxycarbonyloxy)ethyl,2-(5-indanyloxycarbonyloxy)ethyl and the like;alkoxyalkyl-carbonyloxyalkyl such as2-(1-methoxy-2-methylpropan-2-oyloxy)ethyl and like;arylalkyloxycarbonyloxyalkyl such as 2-(benzyloxycarbonyloxy)ethyl andthe like; arylalkenyloxycarbonyloxyalkyl such as2-(3-phenylpropen-2-yloxycarbonyloxy)ethyl and the like;alkoxycarbonylaminoalkyl such as t-butyloxycarbonylaminomethyl and thelike; alkylaminocarbonylaminoalkyl such asmethylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl such asacetylaminomethyl and the like; heterocycliccarbonyloxyalkyl such as4-methylpiperazinylcarbonyloxymethyl and the like;dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl and the like;(5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl such as(5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl such as(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.

The term "perfluoroalkoxy" as used herein refers to a perfluoroalkylgroup as defined herein attached to the parent molecular group throughan oxygen atom.

The term "perfluoroalkyl" as used herein refers to an alkyl group asdefined herein in which all of the hydrogen radicals have beensubstituted with fluoride radicals.

The term "pharmaceutically acceptable prodrug" as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The term "pharmaceutically acceptable salt" as use herein refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting the free base group with a suitableorganic acid. Representative acid addition salts include acetate,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate,hexanoate, hydrobromide, hydrochloride, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium and the like, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamineand the like.

The term "prodrug" as used herein refers to compounds which are rapidlytransformed in vivo to the parent compound of Formula I and II, forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

The term "thioalkoxy" as used herein refers to an alkoxy group asdefined herein attatched to the parent molecular group through a sulfuratom. Examples of alkoxy include, but are not limited to, thiomethoxy,thioethoxy, and the like.

It is contemplated to be within the scope of the present invention thatprodrugs may be used and subsequently converted in vivo into thecompounds of the present invention.

Asymmetric or chiral centers may exist in the compounds of the presentinvention. The present invention contemplates the various stereoisomersand mixtures thereof. Individual stereoisomers of compounds of thepresent invention are prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of mixtures of enantiomeric compounds followed by resolutionwell-known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a racemic mixture ofenantiomers, designated (±), to a chiral auxiliary, separation of theresulting diastereomers by recrystallization or chromatography andliberation of the optically pure product from the auxiliary or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns. Enantiomers are designated herein by thesymbols "R" or "S," depending on the configuration of subsitiuentsaround the chiral carbon atom.

Geometric isomers may also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon--carbon double bond and designates suchisomers as of the Z or E configuration, wherein the term "Z" representssubstituents on the same side of the carbon--carbon double bond and theterm "E" represents substituents on opposite sides of the carbon--carbondouble bond.

Compounds falling within the scope of Formula I and II include, but arenot limited to,

3-[4-(2-methoxyphenyl)piperazinylethyl]-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-6-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-1-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-5-(3-methylphenyl)thieno[2,3-d]pyrimidine-2,4-dione,and

3-[4-(2-methoxyphenyl)piperazinylethyl]-6-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenyl[3,4-d]pyrimidine-2,4(1H,6H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylfuro[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,and

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;or a pharmaceutically acceptable salt, ester or prodrug thereof.

Preferred Compounds falling within the scope of Formula I and IIinclude, but are not limited to,

3-[4-(2-methoxyphenyl)piperazinylethyl]-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-6-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-1-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione,

3-[4-(2-methoxyphenyl)piperazinylethyl]-5-(3-methylphenyl)thieno[2,3-d]pyrimidine-2,4-dione,and

3-[4-(2-methoxyphenyl)piperazinylethyl]-6-phenylthieno[2,3-d]pyrimidine-2,4-dione,or a pharmaceutically acceptable salt, ester or prodrug thereof.

Synthetic Methods

Abbreviations

Abbreviations which have been used in the descriptions of the scheme andthe examples that follow are: DMF for N,N-dimethylformamide, DMSO fordimethyl sulfoxide, and TEA for triethylamine.

Chemistry

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. The compounds of this invention may be prepared by a varietyof synthetic routes. Representative procedures are outlined in Schemes1-3 where R₁, R₂, R₃, R₄, R₅, and n are previously defined unlessindicated otherwise, R_(X) is alkyl of one to six carbons, and --E is--CN or --CO₂ R_(X). It will be readily apparent to one of ordinaryskill in the art reviewing the synthetic route depicted below that othercompounds within Formula I and II can be synthesized by the substitutionof appropriate reactants and agents in the synthesis shown below.##STR19##

Scheme 1 shows the synthesis of compounds of Formula I and II where R₃is hydrogen or alkyl and X═S. The appropriate 2-aminothiophene wasreacted with a chloroalkylisocyanate in a solvent such as toluene withheating to provide a chloroalkylurea. The chloroalkylurea was reactedwith o-methoxyphenylpiperazine in acetonitrile withdiisopropylethylamine to provide a urea. The urea was reacted withpotassium t-butoxide in ethyl alcohol to provide compounds of Formula Iand II. Reaction of this compound of Formula I with a base such assodium hydride followed by an alkyl halide provided the N-alkylatedcompounds of Formula I and II. This method can also be employed toprepare examples where X═O, S, or NH as described in Matsuda, T. et al.Chem Pharm Bull 1985, 33, 937; Cocco, M. T. et al. Il Farmaco-Ed. Sc.1988, 43, 103; Abdelrazek, F. M. J. Prakt. Chem. 1990, 332, 479; andToja, E. et al. Synthesis 1987, 272, each of which is herebyincorporated by reference. ##STR20##

Scheme 2 shows the synthesis of compounds of Formula I and II where R₃is hydrogen or alkyl and X═NH, S, or O. An appropriately substituted3-aminothiophene or 3-aminofuran, including but not limited to thosedescribed in Gewald, K. et al. Liebigs Ann. Chem. 1984, 1702; Hartmann,H. et al. Synthesis 1984, 275; and Kirsch, G. et al. J. HeterocyclicChem. 1982, 19, 443, is reacted with phosgene and triethylamine in asolvent such as dichloromethane or tetrahydrofuran to give anintermediate isocyanate that is reacted with an aminoalkylpiperazine togive a urea. The urea is cyclized with a base such as potassiumt-butoxide in ethyl alcohol to provide compounds of Formula I and II.Reaction of compounds of Formula I and II with a base such as sodiumhydride followed by an alkyl halide provides the N-alkylated compoundsof Formula I and II. ##STR21##

Scheme 3 shows the synthesis of compounds of Formula I and II where R₃is hydrogen or alkyl, X═S, O, or NH. An appropriately substituted3-aminothiophene or 3-aminopyrrole, including but not limited to thosedescribed in patents U.S. Pat. No. 4,212,806, GB 1587084, and EP 298542,is reacted with phosgene and triethylamine in a solvent such asdichloromethane or tetrahydrofuran to give an intermediate isocyanatethat is reacted with the aminoalkylpiperazine to give a urea. The ureais cyclized with a base such as potassium t-butoxide in ethyl alcohol toprovide compounds of Formula I and II. Reaction of this compound ofFormula I with a base such as sodium hydride followed by an alkyl halideprovides the N-alkylated compounds of Formula I and II.

Depending on the nature of R₁, R₂, R₃, R₄, R₅, --E, n, and --CO₂ R_(X),protection and subsequent deprotection of other reactive groups can berequired to successfully complete the described synthetic sequences.Commonly used protecting groups are disclosed in Greene and Wuts,"Protective Groups In Organic Synthesis," Second Edition (John Wiley &Sons, New York (1981)), hereby incorporated by reference.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples that are intendedas an illustration of and not a limitation upon the scope of theinvention as defined in the appended claims.

EXAMPLE 13-[4-(2-methoxyphenyl)piperazinylethyl]-5-phenylthieno[2,3-d]pyrimidine-2,4-dioneEXAMPLE 1A N-(3-carboethoxy-4-phenylthien-2-yl)-N'-(chloroethyl)urea

A solution of 2-amino-3-carboethoxy-4-phenylthiophene, prepared by themethod of Gewald Chem. Ber. (1966), 99, 94, (2.47 g, 0.010 mol) intoluene (30 mL) was heated to reflux, treated with2-chloroethylisocyanate (1.0 mL, 0.012 mol), stirred for 1 hour, treatedwith a second portion of 2-chloroethylisocyanate (1.0 mL, 0.012 mol),stirred for 1 hour, cooled, and concentrated. The product wascrystallized from ethyl acetate/hexane to provide 2.93 g (83%) yield ofthe title compound.

¹ H NMR (300 MHz, CDCl₃) δ 0.90 (t, 3H), 3.68 (m, 4H), 4.04 (q, 2H),5.25 (br s, 1H), 6.48 (s, 1H), 7.30 (m, 5H), 10.69 (br s, 1H).

EXAMPLE 1BN-(3-carboethoxy-4-phenylthien-2-yl)-N'-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]urea

Example 1A (1.0 g, 2.8 mmol) and 1-(2-methoxyphenyl)piperazine anddiisopropylethylamine (0.65 mL) in acetonitrile (20 mL) were heated toreflux for 16 hours treated with water, and extracted with ethylacetate. The extract was washed with brine, dried (Na₂ SO₄), filteredand concentrated. Purification of the residue on silica gel with 50-75%ethyl acetate/hexane provided 0.70 g of the title compound.

EXAMPLE 1C3-[4-(2-methoxyphenyl)piperazinylethyl]-5-phenylthieno[2.3-d]pyrimidine-2,4-dione

Example 1B (0.70 g, 1.4 mmol) in ethanol (10 mL) was treated withpotassium t-butoxide (0.185 g, 1.6 mmol), heated to reflux for 2 hours,cooled, treated with pH 7 buffer solution (75 mL), and extracted withethyl acetate. The extract was washed with brine, dried (Na₂ SO₄),filtered, concentrated, treated with methanesulfonic acid (0.287 g), andconcentrated. The product was recrystallized from ethanol/diethyl etherto provide 0.59 g of the title compound as the methanesulfonate salt.

¹ H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H), 2.87 (br t, 2H), 3.24 (br q,2H), 3.52 (br m, 4H), 3.78 (br m, 2H), 3.80 (s, 3H), 4.21 (br t, 2H),6.97 (m, 4H), 7.10 (s, 1H), 7.39 (m, 3H), 7.50 (m, 2H), 9.10 (br s, 1H),12.5 (br s, 1H); MS (DCI/NH₃) m/z 463 (M+H)⁺ ; Anal. calcd for C₂₅ H₂₆N₄ O₃ S.CH₄ O₃ S.0.5H₂ O: C, 55.01; H, 5.50; N, 9.87. Found: C, 54.90;H, 5.42; N, 9.84.

EXAMPLE 23-[4-(2-Methoxyphenyl)piperazinylethyl]-6-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dioneEXAMPLE 2AN-(3-carboethoxy-5-methyl-4-phenylthien-2-yl)-N'-(chloroethyl)urea

A solution of 2-amino-3-carboethoxy-5-methyl-4-phenylthiophene, preparedby the method of Gewald, (5.22 g, 0.020 mol) in toluene (50 mL) wasprocessed as in Example 1A. The product was recrystallized from ethylacetate/hexane to provide 5.94 g (81%) of the title compound as a whitesolid.

¹ H NMR (300 MHz, CDCl₃) δ 0.78 (t, 3H), 2.11 (s, 3H), 3.69 (m, 4H),3.93 (q, 2H), 5.30 (br s, 1H), 7.15 (dd, 2H), 7.33 (m, 3H), 10.65 (br s,1H).

EXAMPLE 2BN-(3-carboethoxy-5-methyl-4-phenylthien-2-yl)-N'-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-urea

A solution of Example 2A (0.60 g, 1.6 mmol),1-(2-methoxyphenyl)piperazine (0.84 g, 6.5 mmol) anddiisopropylethylamine (0.35 mL) in acetonitrile (25 mL) was processed asin Example 1B. Purification of the crude product on silica gel with 2%triethylamine 50% ethyl acetate/hexane provided 0.53 g of the titlecompound.

EXAMPLE 2C3-[4-(2-methoxyphenyl)piperazinylethyl]-6-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione

Example 2B (0.53 g, 1.0 mmol) and potassium t-butoxide (0.136 g, 1.2mmol) in ethanol (10 mL) was processed as in Example 1C to provide 0.37g of the title compound as the methanesulfonate salt.

¹ H NMR (300 MHz, DMSO-d₆) δ 2.22 (s, 3H), 2.30 (s, 3H), 2.85 (br t,2H), 3.22 (br q, 2H), 3.43 (br m, 2H), 3.54 (br d, 2H), 3.76 (br d, 2H),3.79 (s, 3H), 4.17 (br t, 2H), 6.96 (m, 4H), 7.29 (m, 2H), 7.39 (m, 3H),9.10 (br s, 1H), 12.4 (br s, 1H); MS (DCI/NH₃) m/z 477 (M+H)⁺ ; Anal.calcd for C₂₆ H₂₈ N₄ O₃ S.CH₄ O₃ S:C, 56.63; H, 5.63; N, 9.78. Found: C,56.66H, 5.59; N, 9.60.

EXAMPLE 33-[4-(2-methoxyphenyl)piperazinylethyl]-1-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4-dione

A solution of Example 1C (0.37 g, 0.80 mmol) in DMF (8 mL) was treatedsequentially with 80% sodium hydride (26 mg, 0.88 mmol) and methyliodide (0.050 mL, 0.80 mmol), stirred 3 hours, quenched in water, andextracted with ethyl acetate. The extract was washed with brine, dried(Na₂ SO₄), filtered and concentrated. Purification of the residue onsilica gel with 25-50% ethyl acetate/hexane followed by treatment withmethanesulfonic acid (2 equiv) in ethyl acetate (40 mL) and ethanol (10mL) provided 0.36 g of the title compound as the bis methanesulfonatesalt.

¹ H NMR (300 MHz, DMSO-d₆) δ 2.35 (s, 6H), 2.89 (br t, 2H), 3.25 (br m,2H), 3.51 (br m, 2H), 3.55 (s, 3H), 3.55 (br m, 2H), 3.78 (br d, 2H),3.80 (s, 3H), 4.27 (br t, 2H) 6.97 (m, 4H), 7.22 (s, 1H), 7.40 (m, 3H),7.50 (m, 2H), 9.18 (br s, 1H); MS (DCI/NH₃) m/z 477 (M+H)⁺ ; Anal. calcdfor C₂₆ H₂₈ N₄ O₃ S.2CH₄ O₃ S.0.5H₂ O: C, 49.62; H, 5.50; N, 8.27.Found: C, 49.72; H, 5.55; N, 8.20.

EXAMPLE 43-[4-(2-methoxyphenyl)piperazinylethyl]-5-(3-methylphenyl)thieno[2,3-d]pyrimidine-2,4-dioneEXAMPLE 4AN-[3-carboethoxy-4-(3-methylphenyl)thien-2-yl]-N'-(chloroethyl)urea

A solution of 2-amino-3-carboethoxy-4-(3-methylphenyl)thiophene,prepared by the method of Gewald, (4.0 g, 0.015 mol) in toluene (50 mL)was processed as in Example 1A. Purification of the residue on silicagel with 10-25% ethyl acetate/hexane provided the title compound.

¹ H NMR (300 MHz, CDCl₃) δ 0.93 (t, 3H), 2.37 (s, 3H), 3.70 (m, 4H),4.05 (q, 2H), 5.44 (br s, 1H), 6.49 (s, 1H), 7.11 (m, 3H), 7.21 (t, 1H),10.70 (br s, 1H).

EXAMPLE 4BN-[3-carboethoxy-4-(3-methylphenyl)thien-2-yl]-N'-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-urea

Example 4A (1.0 g, 2.7 mmol), 1-(2-methoxyphenyl)piperazine (0.68 g, 3.5mmol), diisopropylethylamine (0.62 mL) in acetonitrile (20 mL) wasprocessed as in Example 1 B. Purification of the crude product on silicagel with ethyl acetate provided 1.02 g of the title compound.

EXAMPLE 4C3-[4-(2-Methoxyphenyl)piperazinylethyl]-5-(3-methylphenyl)thieno[2,3-d]pyrimidine-2,4-dione

Example 4B (1.02 g, 1.95 mmol) and potassium t-butoxide (0.24 g, 2.2mmol) in ethanol were treated according to Example 1C to provide 0.302 gof the title compound as the bis methanesulfonate salt.

¹ H NMR (300 MHz, DMSO-d₆) δ 2.34 (s, 3H), 2.35 (s, 6H), 2.88 (br t,2H), 3.24 (br q, 2H), 3.49 (br m, 2H), 3.56 (br d, 2H), 3.80 (br d, 2H),3.80 (s, 3H), 4.21 (br t, 2H), 6.96 (m, 4H), 7.06 (s, 1H), 7.17 (m, 1H),7.30 (m, 3H), 9.11 (br s, 1H), 12.5 (br s, 1H); MS (DCI/NH₃) m/z 477(M+H)⁺ ; Anal. calcd for C₂₆ H₂₈ N₄ O₃ S.2CH₄ O₃ S.H₂ O: C, 48.97; H,5.58; N, 8.16. Found C, 49.27; H, 5.65; N, 8.03.

EXAMPLE 53-[4-(2-Methoxyphenyl)piperazinylethyl]-6-phenylthieno[2,3-d]pyrimidine-2,4-dioneEXAMPLE 5A N-(3-carboethoxy-5-phenylthien-2-yl)-N'-(chloroethyl)urea

A solution of 2-amino-3-carboethoxy-5-phenylthiophene, prepared by themethod of Gewald, (0.68 g, 3.1 mmol) in toluene (6 mL) was processed asin Example 1A. Purification the crude product on silica gel with 25%ethyl acetate/hexane provided 806 mg (79%) of the title compound as afoam.

EXAMPLE 5BN-(3-carboethoxy-5-phenylthien-2-yl)-N'-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]urea

A solution of Example 5A (462 mg, 1.37 mmol),1-(2-methoxyphenyl)piperazine (1.7 mmol), diisopropylethylamine (0.29mL) in acetonitrile (5 mL) was processed as in Example 1B. Purificationof the residue on silica gel with ethyl acetate provided 282 mg (41%) ofthe title compound.

EXAMPLE 5C3-[4-(2-methoxyphenyl)piperazinylethyl]-6-phenylthieno[2,3-d]pyrimidine-2,4-dione

A solution of Example 5B (387 mg, 0.762 mmol) in ethanol (5 mL) wastreated with 1M potassium t-butoxide/THF (0.84 mL), heated to reflux for90 minutes, cooled, quenched with 1N HCl(0.84 mL), and partitionedbetween water and ethyl acetate. The insoluble solid was collected,washed with ethyl acetate, slurried in methanol, treated withmethanesulfonic acid (2 equiv), and concentrated. The product wascrystallized from ethanol to provide 180 mg the title compound as thebis methanesulfonate salt.

¹ H NMR (300 MHz, DMSO-d₆) δ 2.32 (S, 6H), 2.90 (br t, 2H), 3.28 (br q,2H), 3.55 (br m, 4H), 3.80 (m, 2H), 3.80 (s, 3H), 4.27 (br t, 2H), 6.98(m, 4H), 7.34 (t, 1H), 7.44 (t, 2H), 7.66 (s, 1H), 7.70 (d, 2H), 9.12(br s, 1H), 12.5 (br s, 1H); MS (DCI/NH₃) m/z 463 (M+H)⁺ ; Anal. calcdfor C₂₇ H₃₄ N₄ O₉ S₃.5H₂ O: C, 47.56; H, 5.47; N, 8.22. Found: C, 47.36;H, 5.47; N, 8.04.

Examples 6 through 15 may be prepared according to the proceduresdescribed in Examples 1 through 5 and the synthetic schemes anddiscussions contained herein.

EXAMPLE 63-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dioneEXAMPLE 73-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dioneEXAMPLE 83-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dioneEXAMPLE 93-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dioneEXAMPLE 103-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenyl[3,4-d]pyrimidine-2,4(1H,6H)-dioneEXAMPLE 113-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione EXAMPLE 123-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5-phenylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dioneEXAMPLE 133-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylfuro[3,2-d]pyrimidine-2,4(1H,3H)-dioneEXAMPLE 143-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dioneEXAMPLE 153-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-7-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

It is to be understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention that is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

Determination of Biological Activity

In Vitro Binding Assays

For purposes of discussing α₁ -adrenoceptor subtypes, the IUPHARconvention of using lower case letters to define molecular clones andupper case letters to indicate pharmacologically defined adrenoceptorshas been followed. Also, the newly recommended nomenclature foralpha-1(α_(1a), α_(1b), α_(1d)) is used.

Representative compounds of the invention were evaluated forα-adrenoceptor binding affinity in vitro using [³ H]-prazosin as theradioligand and two cloned α₁ adrenoceptors expressed in LTK cells:α_(1b) (hamster), and α_(1d) (rat). Additionally, binding affinityagainst the pharmacologically defined α_(1A) adrenoceptor (ratsubmaxillary gland) was measured.

The cDNA clones encoding the α-1 adrenoceptors (α_(1b) and α_(1d)) wereobtained from TULCO (Triangle Universities Licensing Consortium,Research Triangle Park, N.C.) and inserted into the eukaryoticexpression vector SnaB30. In this vector, expression of the adrenoceptorgene is under the transcriptional control of an SV40 early promoter.Positive drug selection is provided by a neomycin-resistance gene. Mousefibroblast cells (LTK) were transfected with the α₁ expression plasmidsand grown in Dulbecco's modified Eagle's medium (DMEM) containing 10%fetal calf serum and 30 mM G418. Stable G418-resistant parental lineswere generated and successful expression of adrenoceptor protein wasmonitored using radioligand binding techniques. Stable single cellclones derived from the parental lines were screened in adrenoceptorbinding assays to identify clones having high adrenoceptor density.Roller bottle cultures of the cloned lines were used to provide cellmembranes for subsequent adrenoceptor binding characterization studies.A cell line containing the SnaB30 vector expressing the humanerythropoietin gene served as a negative control.

For adrenoceptor binding assays, large scale membrane preparations wereutilized in which 6 million cells were seeded into small (450 cm²)Corning tissue culture roller bottles. 200 mL of DMEM containing 10%fetal calf serum and 300 mM G418 were added to each roller bottle. A 95%air/5% CO₂ gas mixture (sterile) was injected into each roller bottleprior to sealing. The bottles were incubated at 37° C. on a roller rackfor 5 days. Cells were re-fed with fresh medium after 3 days in culture.

On the fifth day of culture, growth medium was removed from cells grownin the roller bottles, and the cells were washed twice with PBS (Sigma,120 mM NaCl, 2.7 mM KCl, 10 mM Na₂ HPO₄ --NaH₂ PO₄, pH=7.4). Cells weredetached from the roller bottles by incubating for 15 minutes at 37° C.in a Tris-EDTA solution (10 mM Tris, 100 mM NaCl, 1 mM EDTA, pH=7.4).The cell suspension from each roller bottle was decanted into preweighedcentrifuge tubes and kept on ice. An aliquot of each cell suspension wasgenerally taken for cell counting. Cells were centrifuged at 3000×G for5 min at 2-4° C., washed with PBS and recentrifuged. The supernatant wasdecanted and the pellet was weighed to determine the wet weight ofcells. Cells were washed a final time in 40 vol 5 mM Tris-HCl, 5 mMEDTA, pH=7.7, centrifuged at 40,000×G for 10 minutes, homogenized in 10mL of 50 mM Tris-HCl, 5 mM EDTA (pH=7.4), and diluted to 40 mL/tube.Homogenates were centrifuged at 40,000×G for 10 minutes. The supernatantwas decanted and the pellets were rehomogenized in 50 mMTris-HCl(pH=7.4) and centrifuged as before. The supernatant wasdecanted, the homogenate was resuspended in 6.25 volumes (per gram wetweight) of 50 mM Tris-HCl, and aliquots of the pooled homogenates werefrozen in liquid nitrogen and stored at -70° C. until the time of assay.Rat submaxillary glands were used for α_(1A) adrenoceptors and wereprepared essentially as described (Michel, A. D., Loury, D. N. andWhiting, R. L., Brit. J. Pharmacol. 98: 83-889 (1989)), hereby fullyincorporated by reference.

Receptor binding assays for α-1 adrenoceptors were performed essentiallyas described by Greengrass and Bremner (Eur. J. Pharmacol. 55: 323-326(1979)). Briefly, plastic Bioblocks™ (DBM Scientific, Valencia, Calif.)were incubated at 25° C. for 50 minutes with 500 mL of membranehomogenate (diluted with an additional 96 volumes (for clonedadrenoceptors, 12 volumes for submaxillary gland)) in 50 mM Tris-HClbuffer (pH=7.7 at the time of assay), 450 mL of [³ H]prazosin (0.2 nMfinal concentration, 75-85 Ci/mmole, DuPont-NEN Corp., Boston, Mass.),and 50 mL of either water (for total binding) or 10 mM phentolamine(final concentration, for non-specific binding). Followingequilibration, bound radioligand was separated from free on GF/B filters(presoaked in 0.5% polyethyleneamine) using either a Brandel or Packardcell harvester. Radioactivity was determined by standard liquidscintillation techniques. Data were analyzed as previously described(Hancock, A. A., Kyncl, J. J., Martin, Y. C. and DeBemardis, J. F., J.Receptor Res. 8: 23-46 (1988)).

Table 1 presents receptor binding assay values for compounds of thepresent invention as compared to known nonselective, α₁ adrenoceptorantagonists terazosin and tamsulosin. The results show that thecompounds of the present invention bind to the α₁ -adrenoceptor and showspecificity for the α_(1d) adrenoceptor.

                  TABLE 1                                                         ______________________________________                                        Radioligand Binding Ki (nM)                                                        Example  .sup.α 1A .sup.(Rat)                                                                 .sup.α 1b .sup.(Hamster)                                                        .sup.α 1d .sup.(Rat)                 ______________________________________                                        terazosin  0.823        0.689    1.01                                           tamsulosin  0.028  0.204 0.068                                                1 2.43 3.41 0.213                                                             2 1.97 2.44 0.251                                                             3 2.62 4.47 0.710                                                             4 3.47 2.74 0.170                                                             5  0.578 1.86 0.361                                                         ______________________________________                                    

In Vivo Determination of Intraurethral Pressure (IUP) in Canines

The intraurethral pressure (IUP) model in aged canines is an acceptedmodel of measuring the effect of prostate smooth muscle contraction onurethral tone. Canines also have an enclosed prostate covering theurethral shaft and thus provide an anatomical correlate with humans.

Beagle dogs (Marshall Farms) greater that 2 years of age and weighingbetween 12 and 15 kg were pre-anesthetized with thiopental sodium 15mg/kg i.v. (Pentothal™, Abbott Laboratories, Abbott Park, Ill.) thenplaced under general anesthesia (isoflurane). A 7F Swan-Ganz ballooncatheter (Multiflex-list no. 41224-01, Abbott) was lubricated with awater soluble jelly, inserted into the urethral orifice and advancedapproximately 40 cm in male dogs (considerably less in females) untilthe balloon tip was placed well inside the bladder. The balloon was theninflated with 1 mL of room air, and the catheter was slowly withdrawnjust past the first resistance that is felt at the bladder neck.Preliminary experiments in which dogs were sacrificed after suchplacement confirmed that this technique results in consistentpositioning of the balloon within the prostatic urethra in males or thecorresponding location in females. The balloon port of the catheter wasconnected to a Gould Statham P23Dd pressure transducer interfaced to acomputerized data acquisition system (Modular Instruments, Inc.,Malvern, Pa.) for the measurement of intraurethral pressure (IUP).

Dogs were then treated with propranolol to block the β-adrenoceptoragonist effects of test agonists. Dose-response curves of theintraurethral pressor effect of epinephrine (EPI) were obtained beforeand after each of up to 3 increasing doses of a test antagonist (i.v.).Fifteen minutes were allowed after each antagonist dose forequilibration before the next agonist dose-response was initiated. Theincrease in IUP caused by a given agonist dose was allowed to return tobaseline before the next dose was given. The estimated antagonistdissociation constant (in vivo pseudo pA₂) was determined by Schildanalysis (Brune, et al., Drug Development Research, 34:267-275 (1995).

The results are shown in Table 2. The results indicate that thecompounds of the invention inhibit EPI induced increases in IUP.

                  TABLE 2                                                         ______________________________________                                        Inhibition of EPI Induced Increase in Canine IUP                                       Example  IUP (pA2)                                                   ______________________________________                                               terazosin                                                                            6.97                                                              tamsulosin 8.91*                                                              1 7.95                                                                        5 8.47                                                                      ______________________________________                                         *add 0.4 if slope adjusted to 1                                          

Spontaneously Hypertensive Rat (SHR) Model

The SHR model historically has been used as a predictor for thehypotensive effects of α₁ adrenoceptor antagonists. Male spontaneouslyhypertensive rats were anesthetized, and the left femoral artery andvein were catheterized for the measurement of mean arterial pressure(MAP) and drug administration respectively. The arterial catheter wasconnected to a Gould Statham p23ID transducer and the pressure waveformwas recorded. MAP (mm Hg) and heart rate (HR, beats/min.) weredetermined on-line using a BUXCO Cardiovascular Analyzer. After a 30minute pre-dose control period, each rat was given one dose of a testantagonist i.v., and the MAP and HR were monitored for an additional 2.5hours. The area under the hypotensive response curve up to 60 minutespost dosing (T₆₀ AUC) was determined using a trapezoidal ruleintegration of the percent change from control arterial pressuredataset. The results are expressed as a pED₅₀ value, which is defined asthe negative log of the dose that produced a hypotensive response of-1250, which constitutes 50% of the area under the curve between SHR andnormotensive rats.

The results are shown in Table 3. The results show that the compounds ofthe invention possess hypotensive activity and can be useful fortreatment of hypertension.

                  TABLE 3                                                         ______________________________________                                        Spontaneously Hypertensive Rat (SHR) Activity                                          Example  pED.sub.50                                                  ______________________________________                                               terazosin                                                                            6.40                                                              tamsulosin 7.22                                                               1 6.17                                                                        5 6.04                                                                      ______________________________________                                    

Pharmaceutical Compositions and Methods of Treatment

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like, Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar--agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar--agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

Compounds of the present invention may be utilized as providing a methodof treating benign prostatic hyperplasia, hypertension, detrusorinstability,and incontinence comprising administering a therapeuticallyeffective amount of a compound of Formula I or II, or a phamaceuticallyacceptable salt, ester or prodrug thereof.

Compounds of the present invention may be utilized by providing a methodof anatgonizing alpha-1D adrenoceptors in a comprising administering atherapeutically effective amount of a compound of Formula I or II, or aphamaceutically acceptable salt, ester or prodrug thereof.

Compounds of the present invention may be formulated into apharmaceutical composition comprising a compound of Formula I or II, ora phamaceutically acceptable salt, ester or prodrug thereof, and apharmaceutically acceptable carrier.

What is claimed is:
 1. A compound having Formula I ##STR22## or apharmaceutically acceptable salt, thereof, wherein R₁, R_(1'), andR_(1") are independently selected from the group consisting of (a) halo,(b) hydroxy, (c) nitro, (d) amino, (e) N-protected amino, (f)haloalkoxy, (g) perfluoroalkoxy, (h) carboxy, (i) O-protected carboxy,() cycloalkoxy, (k) cycloalkyl, (l) cycloalkylalkyl, (m) alkoxy, (n)alkyl, (o) alkenyl, (p) alkenyloxy, (q) alkynyloxy, (r) alkynyl, (s)alkoxycarbonyl, and (t) hydrogen wherein (j)-(s) can be optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of alkoxy, hydroxy, carboxy, O-protected carboxy,amino, N-protected amino, halo, hydroxy, and nitro;n is 2-10; and R₂ is##STR23## wherein U, taken together with the carbon atoms to which it isattached, forms a ring selected from the group consisting of(c) a mono-or disubstituted six-membered heterocycle containing three double bondsand either one, two, or three nitogen atoms, and the mono- ordi-sustituents are independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, and (heterocyclic)alkyl, with the proviso thatat least one of the mono- or di-sustituents is cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl;andwherein R₃ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, and cycloalkylalkyl.
 2. A compound or apharmaceutically acceptable salt, thereof according to claim 1 wherein nis 2-5, U is a mono- or disubstituted six-membered heterocyclecontaining three double bonds and either one, two, or three nitogenatoms, and the mono- or di-sustituents are independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, and (heterocyclic)alkyl,with the proviso that at least one of the mono or di-sustituents iscycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, or(heterocyclic)alkyl; and R₁, R_(1'), and R_(1") are independentlyselected from the group consisting of (a) halo, (b) hydroxy, (c) nitro,(d) amino, (e) N-protected amino, (f) haloalkoxy, (g) perfluoroalkoxy,(h) carboxy, (i) O-protected carboxy, (j) cycloalkoxy, (k) cycloalkyl,(l) cycloalkylalkyl, (m) alkoxy, (n) alkyl, (o) alkenyl, (p) alkenyloxy,(q) alkynyloxy, (r) alkynyl, and (s) alkoxycarbonyl wherein (j)-(s) canbe optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkoxy, hydroxy, carboxy,O-protected carboxy, amino, N-protected amino, halo, hydroxy, and nitro.3. A method of treating benign prostatic hyperplasia, hypertension,detrusor instability, and incontinence comprising administering atherapeutically effective amount of a compound of claim
 1. 4. A methodof antagonizing alpha-1D adrenoceptors in a host mammal comprisingadministering a therapeutically effective amount of a compound ofclaim
 1. 5. A pharmaceutical composition comprising a compound of claim1 and a pharmaceutically acceptable carrier.